The olivo-cerebellar network is the key neuronal circuit in the brain for providing higher-level motor control in vertebrates. The network is based on oscillatory dynamics of inferior olive (IO) neurons controlled by an inhibitory feedback loop with the cerebellar cortex. The oscillations of IO neurons are organized in space and time in the form of oscillatory phase clusters. The clusters provide a dynamical representation of arbitrary motor intention patterns that are further mapped to the motor execution system. Being supplied with sensory inputs, the olivo-cerebellar network is capable of rearranging the clusters in the process of movement execution.
The IO neurons produce quasi-sinusoidal oscillations with definite amplitude and frequency. Action potentials occur at the peaks of the oscillations and, hence, have precise timing properties. The application of extracellular stimuli to the IO neurons does not cause changes in oscillation amplitude and frequency. Stimulation produces only a shift of the oscillation phase and hence a time shift of the corresponding action potential. Moreover, the resulting phase depends only on the strength of the stimulus and does not depend on the point at which the stimulus is applied. This effect is referred to self-referential phase reset (SPR) which has been experimentally observed in intracellular recordings. Accordingly, the phase of the IO oscillators can be quickly reset to a desired phase regardless of the history of phase evolution.
Motor control requires highly coordinated signals driving a large number of muscles. recent studies have shown that motor intention patterns to start an arbitrary movement are formed in the olivo-cerebellar functional network. See, Llinás, R. (1991) in Motor Control: Concepts and Issues, eds. Humphrey, D. R. & Freund, H. J. (Wiley, New York), pp. 223-242; Llinás, R. (2001) I of the Vortex: From neurons to self, The MIT Press; Welsh, J. P. & Llinás R (1997) Prog. Brain Res. 114, 449-461; Ito M. (1984) Cerebellum and Neural Control, Raven Press, New York.
The motor intention patterns represent a set of action potentials inter-coordinated in space and time innervating a corresponding set of motor neurons. To provide the required synchrony of muscle activation, the action potentials must maintain their correct inter-relationships even when traveling to spatially distant muscle areas. The main information characteristic, i.e. the main information-bearing control parameter, is the mutual phase relationship between sequences of action potentials innervating different muscles. The coordination mechanism is provided by the sequence of oscillatory events in the olivo-cerebellar system.
The implementation of a universal control system (UCS) capable of intelligent multi-parameter control based on olivo-cerebellar physiology has been recently proposed. See Kazantsev, V. B., Nekorkin V. I., Makarenko, V. I. & Llinás, R. (2003) Procs. Natl. Acad. Sci. USA 100 (32), 13064-13068.
Inferior olive (IO) neurons, which oscillate at approximately 10 Hz, generate a set of action potentials at the peaks of subthreshold oscillations. See Llinás, R. & Yarom, Y. (1986) J. Physiol. 376, 163-182; Bal, T. & McCormick, D. A. (1997). J Neurophysiol. 77, 3145-3156; Lampl, I. & Yarom, Y. (1993) J Neurophysiol. 70, 2181-2186.
Mutual oscillation phase shifts uniquely define the time shift between the action potentials. Thus, motor intention patterns are formed as the oscillatory phase clusters in the inferior olive. See Kazantsev, V. B., Nekorkin V. I., Makarenko, V. I. & Llinás, R. (2003) Procs. Natl. Acad. Sci. USA 100 (32), 13064-13068; Leznik, E., Makarenko, V. & Llinás, R. (2002) J. Neurosci. 22, 2804-2815. Through olivo-cerebellar inhibitory feedback and sensory inputs, the IO neurons are capable of appropriately reconfiguring their oscillations so as to provide the required phase cluster pattern.
To sustain a given phase cluster, the IO neurons have an internal synchronization mechanism. The dendrite of an IO neuron forms gap junctions with about 50 neighboring cells providing local oscillation synchrony. See Llinás, R. & Yarom, Y. (1981) J. Physiol. Lond. 315, 549-567; Sotelo, C., Llinás, R., & Baker, R. (1974) J. Neurophysiol. 37, 560-571. Such local coupling cannot provide global coherence and the transition from one cluster configuration to another at sufficiently fast time scales. The reset of the IO oscillators' phases occurs due to sensory input signals coming as the effectors' feedback. Accordingly, the inferior olive neurons reconfigure their phases of oscillation, automatically evolving to an optimal cluster configuration.
The analysis of intracellular recordings from IO neurons under in vitro conditions has shown that the phase reset behavior of oscillating IO neurons has an interesting property. In contrast to typical oscillatory systems, the reset phase of an IO neuron is defined only by the characteristics of the resetting stimulus and does not depend on the moment of time (i.e., initial phase) at which the stimulus is applied. See Leznik, E., Makarenko, V. & Llinás, R. (2002) J. Neurosci. 22, 2804-2815. In this sense, the reset is self-referential in that it ignores the “history” of the system evolution. This is a key property which makes the IO neuron oscillators extraordinarily flexible for processing motor commands and adapting to current conditions. Moreover, different IO neuron oscillators even when uncoupled and remotely located from each other can be quickly synchronized in phase upon receiving the same stimulus.
FIGS. 1A-1D show intracellular recordings of spontaneous IO neuron oscillations at 2 Hz interrupted by extracellular stimuli. In accordance with previous results (see Llinás and Yarom, 1986), an extracellular stimulus delivered at the dorsal border of the IO nucleus generated a full action potential followed by a membrane hyperpolarization in nearby neurons. As shown in FIG. 1A, after extracellular stimulation (marked with an arrowhead), the oscillations disappeared for about 750 msec (boxed area 10) and then resumed with a different phase approximately. The membrane potential was approximately 60 mV.
In FIG. 1B, intracellular recordings of spontaneous (dashed black trace) and stimulus-evoked (solid black trace) oscillations from the same cell are superimposed. Their corresponding power spectra are shown below. Note that extracellular stimulation only modified the phase of the spontaneous IO oscillations without affecting their amplitude and frequency.
This electrical behavior could be obtained repeatedly for any given IO cell. In FIG. 1C, six individual intracellular traces of stimulus-evoked oscillations from the same cell are superimposed on the left. Each trace is shown in a different color. Their corresponding power spectra are displayed below. In every recording, the frequency of stimulation-evoked oscillation was the same (2.0 Hz). Note that in each trace the stimulation induced shift in the oscillatory rhythm of the cell is remarkably similar. Oscillations are clearly seen after the stimulus induced reset but can be barely detected before the stimulation.
Moreover, as shown in FIG. 1D, for a given cell, the average of six individual stimulus-evoked oscillations had the same frequency as that of the spontaneous oscillations. When the cell was stimulated by a train of stimuli, the results were similar to those shown for a single stimulus, but the reset time was prolonged (data not shown). Thus, the stimulus-evoked IO oscillations averaged over several trials had the same frequency and amplitude as spontaneous oscillations and differed only in a phase shift. In FIG. 1D, the average of six traces of stimulus evoked oscillations (solid trace) and the recording of spontaneous oscillations (dashed trace) are superimposed. The stimulus-evoked oscillations in the average trace have the same frequency and amplitude as the spontaneous oscillations and differ only in the phase shift.
The phase reset effect in IO neurons has two basic features: (i) the resulting phase after stimulation is independent of the initial phase and can be controlled by the characteristics of the stimulus; and (ii) being stimulated by the same stimulus, different cells oscillating at different phases are reset to the same phase, i.e. synchronized. The key electrical properties of IO neurons are described in Kazantsev, V. B., Nekorkin V. I., Makarenko, V. I. & Llinás, R. (2003) Procs. Natl. Acad. Sci. USA 100 (32), 13064-13068; Velarde, M. G., Nekorkin, V. I., Kazantsev, V. B., Makarenko, V. I. & Llinás, R. (2002) Neural Networks 15, 5-10.